Journal of Ethnopharmacology 140 (2012) 634642

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Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm

Syndrome differentiation in modern research of traditional Chinese medicine

Miao Jiang a , Cheng Lu a , Chi Zhang a , Jing Yang a , Yong Tan a , Aiping Lu a,,1 , Kelvin Chan b,c,
a

Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
Centre for Complementary Medicine Research, University of Western Sydney, NSW 2560, Australia
c
Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia
b

a r t i c l e

i n f o

Article history:
Received 24 October 2011
Received in revised form 22 January 2012
Accepted 22 January 2012
Available online 1 February 2012
Keywords:
Syndrome differentiation
Traditional Chinese medicine

a b s t r a c t
Syndrome differentiation (Bian Zheng) in traditional Chinese medicine (TCM) is the comprehensive analysis of clinical information gained by the four main diagnostic TCM procedures: observation, listening,
questioning, and pulse analysis, and it is used to guide the choice of treatment either by acupuncture
and/or TCM herbal formulae, that is, Fufang. TCM syndrome differentiation can be used for further stratication of the patients conditions with certain disease, identied by orthodox medical diagnosis, which
could help the improvement of efcacy of the selected intervention. In modern TCM research it is possible
to integrate syndrome differentiation with orthodox medical diagnosis leading to new scientic ndings
in overall medical diagnosis and treatment. In this review, the focus is to screen published evidence on the
role of syndrome differentiation in modern TCM research with particular emphasis on basic and clinical
research as well as, pharmacological evaluation of TCM herbal formulary for drug discovery.
2012 Elsevier Ireland Ltd. Open access under CC BY-NC-ND license.

1. Introduction
Currently traditional Chinese medicine (TCM) is an essential part
of the healthcare system in several Asian countries, and is considered a complementary or alternative medical system in most
Western countries (Jiang et al., 2010a). The general practice of
TCM depends on the accurate diagnosis and treatment procedures
known as Bian Zheng Lun Zhi (syndrome differentiation followed
by treatment procedures). Syndrome differentiation is one of most
important concepts in the practice of TCM that consists of a series of
diagnostic procedures. Syndrome differentiation is different from
the conventional diagnosis methodology used in orthodox medical practice. It is the process of comprehensive analysis of clinical
information obtained by the four main diagnostic TCM procedures:
observation, listening, questioning, and pulse analyses. It is used to
guide the choice of TCM treatment using acupuncture and or TCM
herbal formulae, that is, Fufang. Thus the complete TCM process
is known as Bian Zheng Lun Zhi, Treatment based on syndrome
differentiation. Correct TCM syndrome differentiation is the most

Corresponding author at: China Academy of Chinese Medical Sciences, Nnaxiaojie 16#, Dongzhimennei, Beijing 100700, China. Tel.: +86 1064067611;
fax: +86 1084032881.
Corresponding author at: Locked Bag 1797, Penrith, NSW 2751, Australia.
Tel.: +61 291141485; fax: +61 246203291.
E-mail addresses: lap64067611@126.com, lap@jzjt.com (A. Lu),
kelvin.chan@sydney.edu.au (K. Chan).
1
Prof. Aiping Lu is working as Dean and Chair Professor in the School of Chinese
Medicine, Hong Kong Baptist University from February, 2012.
0378-8741 2012 Elsevier Ireland Ltd. Open access under CC BY-NC-ND license.
doi:10.1016/j.jep.2012.01.033

important principle that guides the prescribing of Chinese herbal

formulae (Bao et al., 2010). It is possible to integrate TCM syndrome
differentiation and biomedical diagnosis in modern clinical practice. As shown in Fig. 1, diseases diagnosis shown in the transversal
way for patient classication and TCM syndrome differentiation
shown in the longitudinal way indicate a cross relationship. A
patient can suffer from 2 or more diseases at same time, and one
disease can show 2 or more TCM syndromes. Similarly a patient
can show a mixture of TCM syndromes (2 or more syndrome),
and one TCM syndrome can be shown in different diseases. Moreover, syndrome differentiation is dynamic, and one syndrome could
be altered after TCM treatment according to the previous TCM
diagnostic pattern (symptoms, signs, tongue appearance and pulse
feelings).
The information obtained from syndrome differentiation,
including symptoms, pulse feelings and tongue appearance, is often
considered to be subjective. Patients responses to treatment and
their feelings can be recorded objectively in terms of patients
reported outcomes (PROs), using instruments such as the scaling
ruler and questionnaires (Zhao and Chan, 2005). Recently TCM syndromes were detected and veried in many diseases, including
Fibromyalgia Syndrome (Aliyev et al., 2010), amnestic mild cognitive impairment and Alzheimers dementia (Miao et al., 2009),
hyperlipidaemia (Xue et al., 2010), gastric mucosal dysplasia (S.W.
Shen et al., 2011), thoracic diseases (Fu et al., 2011). Some correlations between certain TCM syndrome and the disease were also
validated: the association between Shen (kidney) deciency syndrome and postmenopausal osteoporosis (Chen et al., 1999), Xue
Yu (blood stasis) syndrome and coronary heart disease (Chen et al.,

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635

Fig. 1. Concept of TCM syndrome differentiation and its correlations to biomedical disease diagnosis. TCM syndrome and biomedical disease are classied basing on different
parameters, and they can be linked to each other as shown; TCM syndrome also exhibits transitional changes during the treatment of the illness.

2011). Such observations have provided the substantial evidence

for the objectiveness of TCM syndrome differentiation.
TCM has its origins in China and the information for the TCM
syndrome differentiation is used in the past by the Chinese based
on the Chinese cultural development and understanding of TCM
and its philosophies. The medical service based on TCM syndrome
differentiation may be difcult to be understood in the west, but in
the recent years where TCM practice outside China is widespread,
the TCM concepts have been adopted and practised gradually.
However scientists in the west may not be familiar with the intricacies of the syndrome differentiation and have generally focused
on phytochemical approaches on Chinese materia medica (CMM)
with no reference on TCM syndrome differentiation research. Yet
recently researchers outside China have demonstrated that the
TCM syndromes can be observed in patients who are not of Chinese origin. For instance, evidence was observed in the distribution
of similar TCM syndromes in Australian and Chinese women with
primary dysmenorrhoea (Zhu et al., 2009); the Shen deciency syndrome could be diagnosed in both German and Chinese menopausal
women under the same diagnostic criteria (Rampp et al., 2008).
TCM syndrome differentiation, if adopted as the diagnostic method
for the substantial part in modern TCM research, would lead to
new scientic ndings for medical sciences. In this review, we have
explored its roles on modern TCM research and particularly focused
on its innovative impacts on medical research.

2. Syndrome differentiation and modern research in TCM

diagnosis
One TCM syndrome differentiation can be observed in different
diseases as identied by western medicine (WM), and different syndrome differentiation can be shown in one WM-disease
(biomedical disease). Thus it is not necessary to have a one to
one correlation between the TCM syndrome and the biomedical disease. In the clinical practice in China, both the biomedical
diagnosis for the disease and TCM syndrome differentiation are
often incorporated, and the correlation between the biomedical
disease and TCM pattern is considered as the most important
approach for modern TCM diagnosis research. Fig. 2 indicates how
the correlation between TCM syndrome differentiation (e.g. tongue
appearance or pulse feeling) and the biomedical parameters (the
diagnosis information obtained from laboratory parameters and

omics/biomarkers data related to the biomedical disease) can be

explored and further focused.
Considerable achievements have been made in correlating TCM
syndromes differentiation with measurable modern biomedical
indexes. The observations include: the linkage between sex hormones and Shen deciency syndrome was identied in chronic
nephritis (Zhang et al., 1990); between C-reactive protein and
Han/Re (cold/hot) syndrome in rheumatoid arthritis (RA) (Zhao
et al., 2006); between Qi-Yin deciency syndrome in type 2 diabetes
mellitus patients (Xie et al., 2011); between carotid intimamedia
thickness (IMT), triglyceride (TG) and blood rheology with certain
TCM syndrome (Lei et al., 2009); between blood stasis syndrome
score with 24-h urine protein ration, cholesterol, estimation of
glomerular ltration rate (eGFR) in the primary glomerular diseases
(Li et al., 2009); between the bone mineral density and Shen deciency syndrome in chronic obstructive pulmonary disease (COPD)
(Wang et al., 2005); between serum level of eosinophil cationic
protein in asthmatic patients and the development of heat syndrome manifestations (Hsu et al., 2003); between the decrease in
skin electrical conductance and the severity of Qi deciency syndrome (Yu et al., 1998). More studies are in progress to explore the
correlations between TCM syndrome and the biological indexes.
We believe that, following the use of data mining techniques and
bioinformatics approaches, the biological basis of TCM syndrome
would be further claried.
Systems biology approaches have recently been innovatively
utilized in the TCM syndrome differentiation studies. Systems
biology is similar to the views of the holistic approaches and
syndromes differentiation of TCM. It has been pointed out these
systems biology-based diagnostic principles can be used as pillars of the bridge between TCM and biomedicine (Xue et al., 2006;
van der Greef et al., 2010). From the view of the gene expression prole, the TCM syndrome differentiation has close intrinsic
relations with not only the difference of gene expression but
also the gene polymorphisms. Therefore, applying the advanced
microarray and sequencing techniques can help clarify the biological basis of TCM syndrome (Xue et al., 2006). By using the
microarray, RT-PCR and ELISA technologies, it was explored that
Shen Yang deciency syndrome is involved in special SNP linkage
disequilibrium (LD) in the intragenic level (Ding et al., 2009b), and
the marked low level of energy output in Shen Yang deciency
syndrome may be primarily attributed to the insufcient activity of the MAPK pathway (Ding et al., 2009a). The correlation of

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Fig. 2. Application of TCM syndrome differentiations in modern innovative research in TCM. The correlation can be applied either between TCM symptoms (including tongue
appearance and pulse feeling) and biological parameters in biomedicine, or between TCM syndrome (assemblages of clinical manifestation) and omics parameters/biomarkers
in biomedicine.

inammatory- and immune-related genes with coronary heart disease (CHD) patients of blood-stasis syndrome was revealed at the
level of nucleic acid, and the target gene IL-8 could play a role
in the pathology of CHD with blood-stasis syndrome (Ma et al.,
2009). The cold syndrome was discovered to be possibly caused by
the physiological imbalance and/or the disorder of metabolite processes by the microarrays technology (Yang et al., 2007). Similarly,
a wide range of metabolomics analytical techniques are widely
used in the modern research of TCM syndrome (Liang et al., 2010).
For example, the metabolomics method, ultra performance liquid
chromatograph/time of ight mass spectrometer (UPLC/TOF-MS)
was successfully used in evaluating the animal model of TCM syndrome differentiation (Tong et al., 2011). A urinary metabolomics
method based on ultra-performance liquid chromatography coupled with mass spectrometry (UPLC/MS) was developed to study
metabolomic characters of the Shen Yang deciency syndrome rats
(X. Lu et al., 2011). By metabolite proles measured in plasma using
GC/MS, molecular differences between the Cold and heat syndrome
in RA patients were found, which suggest differences in apoptotic
activity (van Wietmarschen et al., 2009). Using the GC/TOF-MSbased metabolomic method, the metabolites contributing most to
the classication between the Xin blood stasis obstruction and Qi-Yin
deciency syndrome rats were identied as the potential biomarkers (Yan et al., 2009). A urinary metabolomics method based
on the ultra-performance liquid chromatography combined with
quadrupole time-of-ight tandem mass spectrometry (UPLC Q-TOF
MS) was used to evaluate the efcacy and study the mechanism of
TCM herbal preparation in treating the blood stasis syndrome (Zhao
et al., 2008). Proteomics has recently received extensive attention in the area of medical diagnosis and drug development, and
the proteomics data could also contribute to the TCM syndrome
differentiation research. We believed that with further development of analytical techniques, systems biological approaches
and omics data will greatly promote TCM syndrome differentiation research and be benecial to the modernization of TCM
diagnosis.

The correlation exploration studies between TCM syndrome

differentiation and biomedical disease not only elucidate the biological basis for TCM syndrome differentiation, but also can help
innovative study in biomedicine, and more importantly help the
further accurate stratication of patients for intervention selection by fully integrating of the TCM syndrome differentiation and
biomedical diagnosis.

3. Syndrome differentiation and modern clinical research

in TCM
More and more clinical trials of TCM have been conducted and
reported in China and abroad in the last decade with diversied
results (Jiang et al., 2010a). The key issue in clinical research in TCM
is how to apply TCM syndrome differentiation in the clinical trial
design. TCM syndrome differentiation, as a method of patient stratication, could change clinical trial strategy and help design better
clinical trials. This could be included in the clinical trial, as TCM
syndrome differentiation, can help choose the most appropriate
patients for the intervention. The concept behind TCM syndrome
differentiation and biomedical disease based efcacy evaluations
may optimize clinical trial design by identifying the responsive
cases which might be categorized in a certain TCM syndrome differentiation. Fig. 3 indicates, in a clinical trial focusing on a disease,
there will always be the responsive and non-responsive cases to
one intervention. The comparison analysis between the responsive
and non-responsive cases can help detect the effectiveness related
symptoms and signs (which might be different from typical TCM
syndrome differentiation but homologous with and rooted from
TCM syndrome differentiation). Then a next round of clinical trial
can be conducted focusing on this subgroup of patients with the
positively related symptoms and signs as part of inclusion criteria. We can therefore anticipate that a higher effective rate would
be obtained in the second round of clinical trial since the patients
have been further stratied with the responsive related factors. This

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637

Fig. 3. Application of the TCM syndrome differentiation in clinical trial design. The left portion illustrates the intervention with TCM syndrome can be obtained from a clinical
trial by comparing the differences between responsive cases and non-responsive cases, and the incorporation of the TCM syndrome information for further verication in
second clinical trial. The right portion indicates that if the clinical trial is aimed to evaluate the effectiveness of an old drug, the old drug can be assessed to have more specic
indication after incorporation of TCM syndrome differentiation via the new clinical trial design.

innovative clinical trial design can also be used for the clinical efcacy evaluation of old drug to renew its indication (the right
part in Fig. 3). Recently a two-stage clinical trial of TCM therapy
for the management of RA has been designed (Zhang et al., 2011).
The stage one trial is an open-label trial and aims to explore what
groups of TCM information (such as symptoms) correlates with better efcacy, and the stage two trial is a randomized, controlled,
double-blind clinical trial that incorporates the efcacy-related
information identied in the stage-one trial into the inclusion criteria. This design, though not dening the TCM syndrome criteria,
does include TCM syndrome differentiation concept.
In the clinical studies which employed TCM syndrome differentiation in the design, the desirable outcomes are found easier
to be achieved. For instance, in a double-blinded and randomized
clinical trial, Fufangkushen enteric-coated capsule was proved to
be similarly effective and safe in the treatment of active ulcerative
colitis (UC) with TCM syndrome of damp-heat accumulation interior compared with a mesalamine enteric-coated tablet, and it even
indicated preferable effect in the treatment of UC with inamed
area of the left hemicolon (Gong et al., 2011). In a prospective RCT,
Tanreqing Injection was proved to be able to improve the TCM signs
and symptoms in the patients with acute exacerbation of chronic
obstructive pulmonary disease and TCM syndrome of retention of
phlegm and heat in Fei (Lung) (Li et al., 2010). Good effectiveness was
objectively shown in the TCM treatment of childrens respiratory
syncytial viral pneumonia with phlegm-heat blocking Fei (Lung) syndrome in 206 children with a single-blinded multi-center, blocked,
randomized and parallel-controlled trial (Yang et al., 2009). In a
108 patients with psoriasis of blood-heat syndrome clinical study, a
new Pulian Ointment (NPLO) showed a reliable therapeutic efcacy
and good safety for the treatment of psoriasis with TCM blood-heat
syndrome (Zhou et al., 2009). Another RCT proved the denite therapeutic effect and high safety can be achieved in using the TCM
therapy to treat RA with syndrome of damp-heat obstruction (H.B.
Shen et al., 2011). A clinical investigation indicated that a more
effective treatment rate could be achieved for RA patients when

co-diagnosed and treated based on their TCM syndrome differentiation classication (Zha et al., 2006). Though some clinical trials
and systematic reviews reported that it was difcult to show rigorous evidence for the effectiveness and safety of herbal medicine
(M.M. Zhang et al., 2004; Chen et al., 2006; Leung et al., 2006), randomized controlled clinical trials (RCTs) with specic assessment
criteria and diagnostic criteria are considered as being able to close
the gap between TCM and evidenced-based medicine (Zheng et al.,
2011). Therefore the incorporation of TCM syndrome differentiation for further stratication of the patients could improve the
efcacy of a certain intervention in clinical practice.
The safety evaluation of a TCM intervention can be conducted
basing on the same principle. Through the thousands of years of
experience based practice, a full-grown TCM intervention usually
possesses a good safety prole when used for its corresponding
TCM syndrome differentiation. Some symptoms are proved to be
predictive factors/risk factors for the drug adverse reactions (ADRs)
in RA patients treated with both TCM and biomedical combination therapy (Jiang et al., 2011b), and there have been documented
evidence showing correlations between gastrointestinal ADRs with
clinical efcacy in RA patients treated with biomedical combination
therapy (Jiang et al., 2010b). Thus the evaluation of TCM treatment
efcacy and safety should focus on a specic subgroup of patients
with its corresponding TCM syndrome differentiation.
4. Syndrome differentiation and modern pharmacological
research in TCM
The clinical application of Chinese herbal medicine (CHM)
should be based on syndrome differentiation in TCM, and the
pharmacological evaluation of CHM should be also based on the
TCM syndrome differentiation. To clarify the CHM pharmacological activity is not only the requirement for TCM globalization, but is
also important for guiding the clinical application of CHM. Thus the
method of characterizing of the TCM syndrome differentiation in
animal disease models becomes the key issue in pharmacological

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evaluation. In the past years, some studies have reported that some
conditions induced by chemicals could be considered having similar TCM syndrome differentiation since the conditions showed
certain clinical manifestations similar to the patients with the TCM
syndrome differentiation, and the condition could be reversed by
the corresponding CHM. For example, TCM Pi deciency (Pi Xu) rat,
induced by reserpine administration, could be treated with the
Lizhong Pill which can reinforce the decient Pi (Zhao et al., 2011).
Rodents with liver injury induced by carbon tetrachloride could be
regarded as suffering from the dampness-heat syndrome (Cao et al.,
2009). A novel mice model induced by chronic intermittent hypoxia
showed similar symptoms and signs accorded with the clinical features of Deciency of both Qi and Yin syndrome (Chai et al., 2010).
Rats with subcutaneous tumor of pancreatic cancer can be regarded
as suffering from syndromes of Damp heat (Shi-Re) and Pi deciency
(Dai et al., 2010). Based on the animal models with induced TCM
syndrome differentiation, pharmacological evaluations have been
conducted on CHM. Using the Qi deciency and blood stasis syndrome rats model, the effects of Buyang Huanwu decoction on CHD
were proved to be associated with the inhibition of C-reactive protein (CRP) and vascular endothelial regulators (Zhang et al., 2010).
More directions on how to integrative TCM syndrome and biomedical disease in animals have been conducted (Chai et al., 2009) and
the establishment of the disease with TCM syndrome differentiation induced model could provide new concepts and method for
evaluation of CHM (Ma and Zhai, 2010).
However the TCM syndrome differentiation is not only
complicated, but also based on the information generated by
experience-based TCM diagnostic methods mainly from diagnosis through interrogation. Thus the pharmacological evaluation on
CHM using these types of animal models could provide an alternative way. However it is necessary to develop more TCM syndrome
differentiation animal models based on the phenotype clinical
manifestations, and veried with the positive responses induced
by the TCM syndrome differentiation corresponding CHM. On the
other hand, following the development of biomedicine, one important way to clarify the TCM syndrome differentiation characteristics
of the animal disease model in the pharmacological evaluation
is to compare the differences between the responsive and nonresponsive animals to a certain intervention, and to nd out the
responsiveness-related biomedical characteristics, which can be
regarded as the essentials of the corresponding TCM syndrome differentiation. The biomedical characteristics can then be applied as
the text parameters for the pharmacological evaluation of a related
CHM.

5. Syndrome differentiation and modern new drug

discovery in TCM
In orthodox medical practice any agent intended for human use
as a prescribed drug often consists of a single chemical compound
for the treatment of a specic disease diagnosed by biomedical
method. In TCM practice after diagnosis of patients conditions
according to specic syndrome differentiation, multiple component Fufang consisting of several CMM is prescribed to restore
the patients imbalanced conditions. The multiple compounds in
Fufang, targeting on the biological network within the human body
can be analysed for new drug discovery if their concerted actions
can be recorded in terms of network pharmacology that links with
the biological networks of disease, the drug and drug-disease interaction, and could provide the leads of becoming the next paradigm
in drug discovery as described by Hopkins (2007). Hence new drugs
can be discovered from the old drugs if they can be redened
with the newly prescribed conditions which are based on the integration of biomedical disease and TCM syndrome differentiation.

Syndrome differentiation should be taken into consideration in

new drug discovery since TCM syndrome differentiation is involved
in diagnosis and treatment in TCM practice. All natural products
can act as drugs for the treatment of disease when they are found
effective in certain patients with corresponding TCM syndrome,
and such approaches focus on tailoring drug treatment prescribed
to the patients. Thus it is possible to nd new indication of a certain drug in a clinical trial based on TCM syndrome differentiation
concept. Consecutive clinical trials can be employed to nd new
drugs by revealing the TCM syndrome related indications of existing old drugs. As shown in the right part of Fig. 3, the ndings
of the new indication can be realized by determining what are
positively or negatively related to the effectiveness. The correlated
factors could be obtained by comparing the differences between the
effective cases and non-effective cases in the view of syndrome differentiation. Our previous study showed that RA patients with cold
syndrome had a signicantly higher response rate to the biomedical
therapy (consisting of diclofenac, methotrexate, and sulfasalazine)
than RA patients with hot syndrome (Lu et al., 2009), and this can
give rise to the therapy that could lead to a new drug discovery
since its indication was redened with the TCM cold syndrome. All
medicines should be rigorously tested in the clinical trials (Angell
and Kassirer, 1998; Tsang, 2007), and potential clinical trials based
on TCM syndrome differentiation could be a way for new drug
development by referring to the biomedical disease indications.
Network pharmacology, a systems biology based methodology,
is a new TCM approach to drug design that encompasses the construction of disease network, drugtarget network, drugdisease
network. It offers the concept of drug discovery that simultaneously
considers the improvement of clinical efcacy and reduction of side
effects and toxicity, which are the most important reasons for failure in R&D of new drug (Sams-Dodd, 2005; Hopkins, 2008). Based
on TCM network pharmacology, the molecular network of disease
diagnosed by TCM syndrome and pharmacological network that
relates the herbal formula (mainly multiple herbal compounds) are
important key factors for consideration. Information for a disease
could be collected and accumulated to build up the molecular network of that particular disease as identied in orthodox medicine.
For example, the molecular network has been built up on rheumatoid arthritis (RA) (Wu et al., 2010). The network of a disease could
be linked to locate the corresponding pharmacological network
of drug treatment (intervention) by merging the disease network
with the intervention network. In recent years, scientists focused
on the molecular network build-up using TCM pattern differentiation for certain diseases (Zhao et al., 2010). For instance, RA can
be differentiated into two major TCM patterns: cold and hot patterns, which can be shown in terms of molecular networks (Jiang
et al., 2011a). Separate TCM formula used for intervention of RA of
cold or hot patterns, with multiple herbal compounds, are targeting
on separate biological networks pharmacologically. Thus buildingup of pharmacological network of TCM formula is a good way to
nd new potential multiple compound medicines for a TCM syndrome in a disease or new targeted TCM syndrome for an old drug.
Advance information on genomics, proteomics and metabolomics
has enabled scientists to correlate proper methodology for building
up the molecular pharmacological network in combinational TCM
therapy. For example, we have successfully combined text-mining
with bioinformatics to build up the functional networks for Salvia
miltiorrhiza radix (SM) and Panax notoginseng radix (PN) combination in the TCM intervention of coronary heart diseases by the
SMPN herbal-pair formula (Gao and Aiping, 2011).
By linking the molecular disease network, TCM syndrome with
the pharmacological network of the potential TCM formula, we can
locate which formula would be the best in treating the disease
with the identied TCM syndrome and in terms of molecular disease network. Such approach will further help to choose the right

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639

Fig. 4. Application of TCM syndrome differentiation and new drug discovery. A patient with a certain disease associated with TCM syndrome may show certain characteristics
in the disease-based network and syndrome characteristics in TCM syndrome network. Based on the network pharmacology of a drug built up by systems biology approaches,
the new drug could be developed with targeting on specic TCM syndrome in a certain disease by comparing and merging the pharmacological network of a new drug candidate
with the characteristics in the TCM syndrome network in a disease-based network. The pharmacological networks of potential candidate A, B and C were merged with the
molecular networks of TCM syndrome A, B and C in the disease respectively.

new drug candidates for further pre-clinical study (discovering new

chemical compounds) or clinical study (for dening the new indication with TCM syndrome for that old drug). As shown in Fig. 4,
TCM syndrome differentiation network incorporated in the disease
biological network can: generate the investigating path for potential drug candidates or locate existing old drugs via the merging
of TCM syndrome with identied disease biological network and
identify the pharmacological networks of tested candidates. More
importantly, there are many herbal formulas such as the SMPN
herbal pair, and the herbal formulas would be a great source for
new multiple compound drug discovery. The network pharmacology would be helpful in nding the right multiple compound drug
candidates from herbal formula for further new drug development.

networks (Wang and Cheng, 2005) and the ensemble empirical

mode decomposition (Yan et al., 2011).
Comprehensive equipment or diagnostic systems on combination of four examination methods, including inspection,
auscultation, interrogation, and pulse-feeling and palpation for
TCM syndrome differentiation are being developed by integrating
modern medical techniques. One such system had entered the market in China last year (http://www.daosh.com/s.asp?id=79). The
feasibility and usefulness of this system is being tested. We believe
that from this launch, more novel diagnostic equipment for TCM
syndrome differentiation will be developed and assessed for their
usefulness in TCM syndrome differentiation in the near future.
7. Major issues in modern TCM syndrome differentiation
research

6. Syndrome differentiation and novel medical equipment

development in TCM
The advances in medical technological diagnosis equipment
used in monitoring of disease patterns can certainly help modernization of TCM diagnosis and treatment processes. It is
recognised that TCM syndrome differentiation is a complicated
and experience-based process. To have a generalised and agreed
method of diagnosis using novel diagnostic equipment on TCM
tongue and pulse diagnosis will assist further development towards
objective measurement.
Tongue appearance has some specic features and could be simplied for clear identication in clinical practice though there is a
relatively poor consistency in the results of TCM syndrome differentiation due to the subjective nature of assessing complicated tongue
appearance and pulse (G.G. Zhang et al., 2004; Zhang et al., 2005).
Previous study suggests that tongue coating and tongue body
colour might be used to help identify a subset of RA patients for certain interventions (Jiang et al., 2011c). More efforts are needed for
research into the diagnostic equipment for accurate measurement
of the tongue and pulse diagnosis. It was reported that a digital
analysis instrument for the tongue image can objectively describe
the tongue features of patients with different syndromes of lung
cancer (Su et al., 2011). Efforts have been made to build up a feasible and effective model for pulse analyses in order to facilitate its
clinical application. These models were introduced or constructed
based on an articial neural network (Tang et al., 2012), Bayesian

TCM focuses attention to the integrity of the whole human

body and its interrelationship with nature. The component parts of
the human body are inseparable and are functionally coordinative
and mutually benecial whilst affecting each other pathologically.
Modern biomedical research has entered an era of integrating
various research technologies and methods to analyse difcult biological problems at molecular level as a whole, which is shown
by studies in terms of genomics, metabolomics and proteomics.
Accordingly the application of molecular biology is to study life
phenomena and nature of diseases, governing and controlling the
development and progression of systems processes. Thus modern
research on TCM syndrome differentiation should lead to better
progress and understanding of TCM diagnostic approaches. However, there has been few progress in research based on the modern
TCM syndrome differentiation. Recently more issues have been
taken into consideration for clinical trial design, systems biology technique application and data mining approach applications.
These will form the major areas for the improvement of modern
TCM syndrome differentiation research.
The key challenge in TCM syndrome differentiation research is
how to standardize the diagnostic procedure for syndrome. TCM
syndrome is differentiated from the clinical manifestations, and
the diversied manifestations would make the TCM syndrome
in a patient appearing in syndrome combination or mixed syndromes (we can dene the simple syndrome as a syndrome unit
in a patient). Some clinical manifestations for TCM syndrome

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differentiation are subjective, such as pulse feelings, which might

provide different understandings about the pulse feelings in the
syndrome differentiation by different doctors. Therefore modern
TCM syndrome differentiation research should focus on the typical (easy to be differentiated) and most important TCM syndromes
in a disease. For example, RA syndrome research should focus on
cold and hot syndrome as they are most important syndromes for
RA, similarly Xue-Yu syndrome should be related to coronary heart
disease. In some instance, major objective clinical manifestations
are considered as bases for TCM syndrome differentiation understandable and simpler. For example, the cold and hot syndromes
in RA were differentiated by analysing 13 symptoms, which are
objective measures in the score scale system as assessment for
evaluation purposes (Lu et al., 2009). Another way for modern TCM
syndrome differentiation research is to dene the corresponding
TCM syndrome when it has positively responded to the intervention (drug treatment or other therapy). In TCM, the choice of herbal
formula is closely related to the TCM syndrome, that is, the herbal
formula must be effective in treating the patients if they are correctly differentiated according to TCM syndrome. Similarly, the
TCM syndrome in the responsive case to an intervention should be
the corresponding TCM syndrome for that intervention. At present
very limited examples can be identied to be corresponding to TCM
syndrome for many interventions (biomedicines included). Therefore the exploration of TCM syndrome via clinical trials that are
linked to biomedical diagnosis should be the key topics in modern
TCM syndrome differentiation research.
A properly conducted clinical trial is one of the most important
methods that measure the success of conventional medical practice and clinical trials involving TCM syndrome differentiation will
be the most important method to assess the efcacy of TCM treatment in the future. Due to the complicated and experience-based
involvement in the TCM syndrome differentiation, it is preferable
to start the TCM syndrome differentiation research at a level that
can be incorporated in clinical trial to demonstrate the importance
of stratication into different TCM syndromes amongst patients. An
example to illustrate such approach would be to focus on the RA, a
disease that has denite measureable clinical/biomedical features
in conventional medical practice. TCM syndrome differentiation
related information can be collected from thousands of RA patients
from either expert consensus on the TCM syndrome differentiation
or from TCM syndrome differentiation generated using statistical
analysis (Li et al., 2006; Lu, 2006). This two stage clinical trial design
including TCM syndrome differentiation concept can be integrated
(Lu and Li, 2010; Zhang et al., 2011) into the clinical trial (see Fig. 4).
Systems biology is a general trend of contemporary scientic
development (Wang et al., 2009). The advances of the Omics revolution and methodology in the post-genomic era of life science
research, bioinformatics and systems biology have all collectively
offered an opportunity to integrate multi-dimensional and multiple
data from medical practices. The capturing of these unprecedented
opportunities and challenges will provide a platform for research
to understanding of the principles of TCM practice. Thus systems
biology approaches are expected to open the way to a new convergence of TCM syndrome differentiation information. By analysing
microarray, metabolomic data obtained from literature, the TCM
syndrome differentiation could be related to biomarkers or biological networks (Cheng et al., in press; Jiang et al., 2011a; A. Lu et al.,
2011). Furthermore, systems biology approaches can assist in identifying the therapeutic mechanism of multiple component herbal
drugs, including the build-up of the pharmacological networks of
the herbal drugs, which can be merged with the TCM syndrome differentiation network in certain diseases to explore the therapeutic
mechanism and the biomarkers for specic indication.
Confronted with the increasing popularity of TCM and the huge
volume of TCM data, both historically accumulated and recently

obtained, there is an urgent need to explore these resources effectively by the techniques of knowledge discovery in database (KDD)
(Feng et al., 2006). A series of KDD methods are used in existing
knowledge discovery in TCM researches, ranging from conventional frequent item set mining to state of the art latent structure
models. Yet few or no obvious progress has been made in TCM
practice with KDD techniques. Thus the integrated data mining approaches should be used with the extensively integrated
databases, such as the TCM data base in Chinese patients with
TCM syndrome differentiation and clinical observation, accumulated case reports in the TCM clinical practice, PubMed in English
on biomedicine, and PubChem in English on herbal chemistry and
protein targets. We believe that integrated data mining approach
application in analysis of the integrated TCM and biomedical
and chemical databases would lead to progress in modern TCM
research. These may include: the nding of the basic rule for herbal
prescription targeting to the corresponding TCM syndrome differentiation in a certain disease, the build-up of the biological network
of the disease, and the potential pharmacological network of the
herbal prescription.
8. Concluding remarks
Over the past decades, we have identied increasing numbers
of clinical trials on TCM treatment efcacy with unsatisfactory RCT
designs due mainly to the lack of stratication using TCM syndrome
differentiation. We expect higher quality RCT in the future to meet
the needs of modern research and development. Such approaches
will add more weight to the evidence-based medical practice in
TCM. However, it is crucial that the concept of TCM syndrome differentiation should be made understood and substantiated with
biomedical evidence in the medical science arena. We have initiated some background work in these areas. Published data have also
been initiated by biomedical scientists and researchers in China and
worldwide to provide information towards these directions. More
effort will be required to substantiate such ndings to support the
concepts.
The TCM syndrome differentiation uses phenotype-like clinical manifestation to classify patients, which would further assist
in stratication for the intervention in order to improve the efcacy of the intervention based on the TCM syndrome differentiation
related clinical trial strategy. Research in TCM syndrome differentiation will provide the basis of the molecular network of TCM
syndrome differentiation for certain disease types, which will assist
in dening the potential mechanism of Chinese herbal medicines.
The incorporation of TCM syndrome differentiation into biomedical disease diagnosis will lead to a new era in the development
of medical sciences to research in the diagnosis, clinical trial, and
new drug discovery in TCM. The way forward to identify evidencebase of TCM syndrome differentiation in TCM practice requires
multidisciplinary collaborations amongst different professionals,
researchers and scientists of both conventional medical and TCM
practices with expertise from biomedical, bioinformatics, medical,
pharmaceutical and TCM disciplines.
Acknowledgements
This study was supported jointly by the National Eleventh FiveYear Support Project of China (2006BAI04A10), National Science
Foundation of China (Nos. 30825047 and 30902003), and MOST
Innovation Project (No. 2008IM020900).
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Glossary
Syndrome: also called Zheng. It is a state dened by TCM based on its own theory
after analysis on the symptoms, tongue appearance and pulse feelings.
Syndrome differentiation: also called Bian Zheng, or pattern classication. It is a process
to dene the syndrome (Zheng).
Bian Zheng Lun Zhi: it means treatment based on Syndrome Differentiation.
Shen deciency syndrome: one kind of TCM syndromes. It is also called kidney deciency syndrome, and it can be classied into 2 major categories, kidney Yang
deciency and kidney Yin deciency.
Shen Yang deciency syndrome: one kind of TCM syndromes, and also called kidney
Yang deciency syndrome.
Shen Yin deciency syndrome: one kind of TCM syndromes, and also called kidney Yin
deciency syndrome.
Xue-Yu syndrome: one kind of TCM syndromes, and also called blood stasis syndrome.
Fufang: TCM herbal formulae.
Han/Re syndrome: two kinds of TCM syndromes with opposite clinical manifestations, also called cold/hot syndrome, or cold/heat syndrome.
I-Yin deciency syndrome: also called Deciency of both I and Yin syndrome. It is a
combined TCM syndrome consisted of manifestations on both I deciency and
Yin deciency syndromes.
I deciency syndrome: one kind of TCM syndromes.
Shi-Re accumulation interior syndrome: one kind of TCM syndromes. It is also called
TCM syndrome of damp-heat accumulation interior.
Tan-Re zoo Fei syndrome: one kind of TCM syndrome, and also called phlegm-heat
blocking Fei (Lung) syndromei.
Xue-Re syndrome: one kind of TCM syndromes, and also called blood-heat syndrome.
Shi-Re syndrome: one kind of TCM syndromes, and also called damp-heat obstruction
syndrome.
Pi-CSU syndrome: one kind of TCM syndrome, and also called spleen deciency syndrome.
Qi-Xu and Xue-Yu syndrome: one kind of TCM syndrome, and also called Qi deciency
and blood stasis syndrome.
Lizhong Pill: one type of TCM proprietary medicines.
Tanreqing Injection: one type of TCM proprietary medicines.
Buyang Huanwu Tang: also called Buyang Huanwu decoction. It is a TCM formula.
Fufangkushen enteric-coated capsule: one type of TCM proprietary medicines.